Neural Changes after Vision Therapy in Convergence Insufficiency: A Systematic Review

Objective To investigate if the use of vision therapy (VT) in convergence insufficiency (CI) has a significant neural impact and how it correlates with the clinical changes occurring with this option of treatment. Methods A systematic review of the scientific literature was carried out in the PubMed and Scopus databases, where all the scientific literature on the neural impact of VT in CI was analyzed. A total of 17 articles were initially found and a detailed analysis was carried out. After full-text reading, only four studies met the defined inclusion criteria. The following data from them were extracted: CI cases and controls, clinical and neural parameters evaluated, the neural response to VT observed, type of study, and VT performed. The quality of the studies was assessed using the GRADE tool. Results Some neural changes have been reported after VT in CI with the use of functional magnetic resonance imaging (fMRI). Specifically, a modification of the functional activity of some brain areas (especially front fields, oculomotor vermis, and cerebellum) was found. However, contradictory findings in terms of the change in functional activity (increase or decrease) were found that might be associated to differences in fMRI protocols. In the GRADE analysis, serious concerns were found in the categories of risk of bias, inconsistency, indirectness, and imprecision, so the certainty of evidence for each outcome was very low. Conclusion The research performed to this date does not allow confirming if there are neural changes occurring after vision therapy in patients with CI because the quality of the research performed on this issue is very low, with several methodological concerns.


Introduction
Convergence insufciency (CI) is the most common binocular disorder, with a variable prevalence depending on the population evaluated (2.25-33%) [1,2].Patients with CI cannot properly maintain the ocular alignment and focus at near distance [3,4], which causes high levels of symptomatology and hinders the patient's quality of life [5].Te most common symptoms are diplopia, headaches, eye strain, lack of concentration, sleepiness at near vision activities, blurry near vision, foating or mixed words when reading, and even eye pain [6,7].Te Convergence Insufciency Symptom Survey (CISS) is a validated instrument widely used to evaluate these symptoms and to detect CI [8].Besides symptoms, there are several clinical signs associated to the presence of CI, including greater exophoria at near than at distance (diference >4∆), a receded near point of convergence (NPC), reduced positive fusional vergences (PFV) in near vision (≤15∆), a reduced accommodative convergence to accommodation ratio (AC/A), and reduced binocular accommodative facility (BAF), with difculty in focusing through positive lenses (≤3 cycles per minute) [9,10].
Concerning the treatment of CI, accommodative and vergence therapy has been demonstrated to be an efective method to alleviate the symptoms while eliminating the altered signs [9,11,12].Specifcally, ofce-based therapy has been proven as even more efcient than home-based therapy [9].Prisms are also sometimes used but they are inefcient in children [13].
Te symptoms and clinical diagnosis of this condition have been widely studied, but its neural implications are less known.Specifcally, knowledge on the correlation between neural and clinical changes in CI is limited.Indeed, there are few studies on how CI afects the functional activity and neural areas.Some neural changes seem to occur in patients with CI after vision therapy which are characterized by parameters such as spatial extent or BOLD signal within several brain areas, including the frontal, temporal, parietal, and occipital lobes and the cerebellum [14][15][16][17].Learning about the impact of vision therapy techniques on diverse neural parameters can allow the clinician to optimize these procedures and therefore maximize the results obtained with them.
Te objective of this systematic review was to investigate if vision therapy in CI has a signifcant neural impact and how it correlates with the clinical changes occurring with this option of treatment.

Methods
In this study, a search was performed in PubMed and Scopus databases.Te goal of this systematic review was to confrm if vision therapy in CI has a signifcant impact on neural activity characterized by functional magnetic resonance.Te search equation used in both platforms was the following: "convergence insufciency" AND (neural OR "magnetic resonance") AND therapy.Te list of references obtained with the search was analyzed comprehensively and only the articles meeting the following inclusion criteria were considered: (i) clinical trials and pseudo-experimental studies on neural changes in CI with any modality of visual training, (ii) studies conducted in humans without neurological pathology, regardless of age and sex, (iii) studies published in English or Spanish, and (iv) studies including an analysis of neural modifcations after visual training using functional magnetic resonance imaging (fMRI).Studies about neural changes in CI associated to neurological alterations, such as neurodegenerative diseases, neurodevelopmental disorders, or brain damage, were excluded.
After the search was performed, duplicates were removed.Ten, a title and abstract review of the remaining articles was conducted frst, selecting the articles that met the inclusion criteria of this review.Finally, a full-text review of these articles was conducted, extracting the following data from them: author, publication year, number of participants, number of cases with CI and controls, sex, clinical parameters evaluated, neural parameters evaluated, the neural response to vision therapy observed, type of study, and vision therapy performed.
After this, a quality assessment of the articles was conducted using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool, considering the following factors: study design, risk of bias, indirectness, inconsistency, imprecision, and publication bias [18].Specifcally, the risk of bias was evaluated using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) and the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) for randomized trials, respectively [19,20].Te overall quality of the evidence was rated as high, moderate, low, or very low following the guidelines of the GRADE tool [21].

Results
On the initial search, 11 articles were found in PubMed and 12 in Scopus (Figure 1).After removing duplicates, a total of 17 articles were obtained and their title and abstract were comprehensively analyzed.After this evaluation, ten additional articles were excluded as they were not meeting the inclusion criteria of this review.Ten, a full-text review of the remaining 7 articles was performed.Tree of these articles were also excluded (all of them for not being clinical trials nor pseudo-experimental pre-post studies) and only four articles were fnally selected [15][16][17]22].
Te most important data (author and year, characteristics of the sample, clinical and neural parameters measured, type of study, and how the vision therapy was performed) of the selected studies are summarized in Table 1.Tese four studies analyzed a total of 84 patients, of whom 52 presented CI and 32 presented normal binocular vision.Te age range among CI patients ranged from 18 to 35 years.
Te most recent study by Alvarez et al. [17] presented the largest number of participants, both CI and controls, and an equitable distribution in terms of sex.All the studies included the evaluation of the NPC, PFV, the magnitude of the phoria, and symptomatology with the CISS questionnaire.Furthermore, most of studies evaluated the neural response in the front felds, oculomotor vermis, and the cerebellum [16,17,22].Tree of the studies compared a sample of CI subjects with binocular normal subjects [16,17,22].Only the study by Widmer et al. [15] used a sample consisting entirely of CI subjects, but the authors administrated a placebo vision therapy to half of the sample.
Table 2 shows the clinical alterations of CI before vision therapy.Headaches, eye strain, and blurred vision were the most reported symptoms in the studies revised [16,17].Furthermore, NPC, PFV, and CISS score were clinical parameters evaluated in all the studies, with similar results in all of them that were indicative of CI [15][16][17]22].Te persistent presence of symptoms and the altered results of the clinical parameters previously mentioned in the diferent studies showed consistency in the clinical manifestation of untreated CI.Te magnitude of the phoria was also measured by Alvarez et al. resulting in an exodeviation of 4 ∆ greater at near than at distance [17].Tis diference in the phoria is related to the difculties to maintain a proper convergence focusing on near objects.In most of studies, stereopsis was only considered as an inclusion or exclusion parameter, but with careful analysis of its changes.Ocular movement analysis revealed the presence of alterations on the coordination and smoothness of the eyes during convergence [22].
Table 3 shows the neural fndings before vision therapy of the CI subjects.A decrease in BOLD signal, spatial extent, and functional activity compared to binocular normal subjects was found in several regions of interest, including the frontal, temporal, parietal, and occipital lobes and the cerebellum [16,17,22].Te study by Widmer et al. found several areas of activation within the cerebellum and the frontal, temporal, parietal, and occipital lobes [15].
Te clinical parameters analyzed after vision therapy are listed in Table 4. Several binocular parameters, such as NPC, PFV, and the level of exophoria at near, showed an improvement [15][16][17]22].Specifcally, there were an increase of the vergence capacity (>15∆) after the use of vision therapy in CI.Alvarez et al. also confrmed the development of a faster response of eye movements [22].A decrease of the symptoms reported by the participants was observed by using the CISS [15][16][17]22].
Table 5 shows a summary of the neural parameter after vision therapy in CI cases.Tree of the studies analyzed found an increased functional activity of several brain areas when comparing pre-and post-therapy [16,17,22].However, Widmer et al. found that after therapy, some of these areas showed a decreased functional activity [15].
Finally, a quality assessment of the articles retrieved was performed using the GRADE tool for each diferent outcome (neural changes within the frontal, parietal, and occipital lobes, the cerebellum, and the brainstem), as shown in Table 6.Te risk of bias was assessed with the ROBINS-I tool for the three non-randomized studies and the RoB 2 for the only randomized trial retrieved (Table 7), obtaining serious or high risk of bias in all cases.In the GRADE analysis, serious concerns were found in the categories of risk of bias, inconsistency, indirectness, and imprecision, so the certainty of evidence for each outcome was very low.Specifcally, the concerns in inconsistency resided in the heterogeneous and contradictory results.Te low results in the category of indirectness were due to the diferent methodology used in each study as well as to the diferences in the stimuli used to analyze the neural response and diferences in the populations evaluated.For the imprecision domain, the followup periods of the studies were too short and unsuitable for characterizing an efect on the long term and the samples were too small and unrepresentative in most of the studies.

Discussion
Tere is a limited body of literature addressing the neurological implications of convergence insufciency.Te visual system is extremely complex, and the study of neural changes often demands the use of techniques and research approaches that may not always be widely accessible in all instances.In fact, the implication of a multidisciplinary team with medical professionals from areas such as neurology or radiology is necessary in this research area.
Eyes with CI have difculty in coordinating and converging efectively towards a near point, but various      8 Journal of Ophthalmology methods, including the utilization of prisms and lenses, can be implemented to address this difculty.However, the most impactful and successful approach is vision therapy [23].At present, vision therapy stands out as the foremost treatment prescribed in clinical settings, often combined with a 12-week regimen of home exercises [9].

Journal of Ophthalmology
During the assessment of changes in standard clinical parameters, a decrease in breakage and recovery of NPC, along with an increase in PFV, and an improvement in near exophoria have been observed and reported by previous authors, including those analyzed in the current systematic review [7,9,12,13].Moreover, the subjects evaluated in the four studies revised underwent anatomical fMRI tests to rule out the presence of lesions or disorders.Te fndings of these analyses suggested that vision therapy for CI might induce alterations in both clinical metrics and functional neural changes, demonstrating an augmented functional activity in specifc regions.Te reported neural changes were in the cerebellum, the front felds, and the oculomotor vermis [16,17,22].Using vision therapy in subjects with CI helped to improve NPC and PFV, increase the mean peak velocity convergence, and increase the functional activity in the frontal lobe, cerebellum, and brainstem.A correlation between the clinical and the cortical signs was also found.Terefore, treating CI through vision therapy seems to involve neural changes within the plasticity of the neural and muscular system.
Tree of the four studies in this systematic review were carried out by professionals of the same group of investigation and performed vision therapy in a sample of subjects with CI and in binocular normal subjects [16,17,22].Terefore, the same methodology was used in these studies and the results obtained were like each other.As previously mentioned, the fourth study employed a sample entirely of subjects with CI but performing in a subgroup a placebo therapy and in another one a binocular-accommodation vision therapy [15].Tis study found diferent outcomes, which may be probably explained by diferent factors, including diferences in the type of stimuli used while obtaining the fMRI images.Te study by Widmer et al. used a random-dot stereogram stimulus at a fxed distance, presenting a disparity of 480 seconds [15], and although the three remaining studies used two diferent stimuli, both were associated with vergence demands: LED target with a disparity of 2 °, 3 °, and 4 °in the case of Alvarez et al. and two eccentric squares with a disparity of 4 °and 6 °in the case of Alvarez et al. [16,17,22].It should be considered that the type of cortex activation analyzed by functional magnetic resonance difers when using a 3D stimuli (such as a stereogram) versus a 2D stimuli [24], which may explain some of the diferences found between the studies analyzed in the type of neural response after vision therapy.Tis highlights the need for a standardized evaluation of the neural response in studies characterizing the impact of vision therapy in brain activity.Besides the type of stimuli, there may be more methodological diferences that may have contributed to the variability of the results from the diferent studies revised in the current systematic review, such as diferences in the population age or the severity of CI [16,17,22].
Widmer et al. [15] found a decrease in functional activity in the frontal lobe (dorsolateral prefrontal cortex and frontal eye felds), parietal lobe (inferior parietal lobule), occipital lobe (precuneus), and cerebellum (cerebellar vermis) after performing vision therapy only in subjects with CI.Specifcally, patients with CI who underwent placebo therapy (consisting of tasks with no vergence or accommodation demand) did not show this neural efect.Te three remaining studies found an increased functional activity of some of these areas after vision therapy in subjects with CI [16,17,22].Tis result suggests that vision therapy might have some impact on brain function, leading to an improvement of the coordination between the eye muscles and consequently of ocular convergence.Tis heightened functional activity may play a role in enhancing the visual function and may have the potential to positively infuence on the execution of daily visual tasks and overall visual performance.However, more studies are needed to defne the exact relationship between neural changes in CI after vision In terms of the quality of the studies, the analysis with the GRADE tool revealed that the level of quality of the studies revised was very low mainly due to the sample size limitations, the inadequate selection of the control group (no inclusion of CI groups with no treatment or placebo treatment in three studies), and the diferent protocols used to evaluate the neural response.Only the most recent study [17] included an acceptable number of subjects in the CI and control groups, but controls were patients with normal binocular vision and consequently without any type of visual treatment.Besides this, the follow-up was extremely short in most of studies, not allowing us to confrm if the neural changes observed with vision therapy were maintained over time.In any case, it should be considered that there are some limitations to perform this type of studies, such as the difculty in recruiting patients, the lack of consensus on the defnition of the fMRI protocol to follow to better evaluate the neural response to visual exercises, and funding restrictions.It should be noted here that fMRI, despite being a non-invasive test, requires complex medical procedures and a technical and specialized team.Te costs of this technology are usually high, depending on the duration of the scanning, the quantity of image sequences, or the need for contrast.
In conclusion, the studies performed to this date do not allow confrming if there are neural changes occurring after vision therapy in patients with CI because the quality of the research performed on this issue is very low, with several methodological concerns.Indeed, some contradictory fndings have been reported in the neural response associated to vision therapy in terms of functional activity (increase or decrease).Future studies should be conducted on this issue with an adequate selection of the number of patients (sample size calculation) and of the type of control group.In addition, there is a need for studies with larger samples (multicentric studies would be very helpful) using standardized protocols of visual stimulation during fMRI evaluation and evaluating the impact on a longer term to confrm the stability of the neural modifcations induced.

Figure 1 :
Figure 1: Flowchart showing the search process in the current systematic review.

Table 1 :
Main results of the studies included in this systematic review.

Table 2 :
Clinical parameters in patients with CI before vision therapy.

Table 3 :
Neural fndings in patients with CI before vision therapy.

Table 4 :
Clinical parameters in patients with CI after vision therapy.

Table 5 :
Neural fndings in patients with CI after vision therapy.

Table 7 :
Methodological quality outcomes using the ROBINS-I tool and the RoB 2.